This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the last decade, there has been an explosion of new knowledge of the neuroscientific basis of alcohol-seeking behavior. Medications that modulate mesolimbic dopamine pathways by facilitating gamma-aminobutyric function and inhibiting the action of excitatory amino acids should reliably diminish alcohol's rewarding effects. Topiramate (a sulfamate-substituted fructopyranose derivative) has these characteristics. In support of this concept, we have shown in a phase-II-type medications clinical trial that topiramate is significantly superior to placebo at improving drinking outcomes and decreasing craving among (N = 150) alcohol-dependent individuals. Using the carefully controlled environment of the human laboratory, we are using a set of systematic studies to assess directly the mechanistic neuropharmacological processes that are associated with topiramate's anti-drinking effects in alcohol-dependent individuals. This will provide a more comprehensive understanding of the neurobiology of alcohol-seeking behavior and aid in the development of even more effective compounds for the treatment of alcohol dependence. Thus, the specific aims of the project are to: 1) determine the dose relationship of acute effects of topiramate to reduce alcohol effects related to its abuse and addiction potential, 2) determine whether chronic treatment with an acutely effective dose of topiramate produces substantial reductions in alcohol-related cue-induced craving, thereby decreasing the potential for treatment relapse, and 3) determine whether topiramate interactions with and without alcohol are associated with neurocognitive impairment.